TECHNETIUM TC 99M SESTAMIBI

Each 10 mL vial contains a sterile, non-pyrogenic, lyophilized mixture of: Tetrakis (2-methoxy isobutyl isonitrile) Copper (I) tetrafluoroborate - 1 mg Sodium Citrate Dihydrate - 2.6 mg L-Cysteine Hydrochloride Monohydrate - 1 mg Mannitol - 20 mg Stannous Chloride, Dihydrate, minimum (SnCl 2 2H 2 O) - 0.025 mg Stannous Chloride, Dihydrate (SnCl 2 2H 2 O) - 0.075 mg Tin Chloride (stannous and stannic) Dihydrate, maximum (as SnCl 2 2H 2 O) - 0.086 mg Prior to lyophilization the pH is 5.6 to 5.8. The contents of the vial are lyophilized and stored under nitrogen. This drug is administered by intravenous injection for diagnostic use after reconstitution with sterile, non-pyrogenic, oxidant-free Sodium Pertechnetate Tc 99m Injection. The pH of the reconstituted product is 5.5 (5.0-6.0). No bacteriostatic preservative is present. The precise structure of the technetium complex is Tc 99m[MIBI] 6 + where MIBI is 2-methoxyisobutylisonitrile. 11.1 Physical Characteristics Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours. 1 Photons that are useful for detection and imaging studies are listed below in Table 3. Table 3. Principal Radiation Emission Date Radiation Mean %/ Disintegration Mean Energy (KeV) Gamma-2 89.07 140.5 1 Kocher, David, C., Radioactive Decay Data Tables, DOE/TIC-11026, 108(1981). 11.2 External Radiation The specific gamma ray constant for Tc 99m is 5.4 microcoulombs/kg-MBq-hr (0.78 R/mCi-hr) at 1 cm. The first half value layer is 0.017 cm of Pb. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 4. To facilitate control of the radiation exposure from Megabequerel (millicurie) amounts of this radionuclide, the use of a 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of 1,000. Table 4. Radiation Attenuation by Lead Shielding Shield Thickness (Pb) cm Coefficient of Attenuation 0.017 0.5 0.08 10 -1 0.16 10 -2 0.25 10 -3 0.33 10 -4 To correct for physical decay of this radionuclide, the fractions that remain at selected intervals after the time of calibration are shown in Table 5. Table 5. Physical Decay Chart; Tc 99m Half Life: 6.02 Hours Hours Fraction Remaining Hours Fraction Remaining 0 Calibration Time 1.000 7 0.447 1 0.891 8 0.398 2 0.794 9 0.355 3 0.708 10 0.316 4 0.631 11 0.282 5 0.562 12 0.251 6 0.501

Myocardial Imaging: Kit for the preparation of Technetium Tc 99m Sestamibi Injection is a myocardial perfusion agent that is indicated for detecting coronary artery disease by localizing myocardial ischemia (reversible defects) and infarction (non-reversible defects), in evaluating myocardial function and developing information for use in patient management decisions. Technetium Tc 99m Sestamibi evaluation of myocardial ischemia can be accomplished with rest and cardiovascular stress techniques (e.g., exercise or pharmacologic stress in accordance with the pharmacologic stress agents labeling). It is usually not possible to determine the age of a myocardial infarction or to differentiate a recent myocardial infarction from ischemia. Breast Imaging: Kit for the preparation of Technetium Tc 99m Sestamibi Injection is indicated for planar imaging as a second line diagnostic drug after mammography to assist in the evaluation of breast lesions in patients with an abnormal mammogram or a palpable breast mass. Kit for the preparation of Technetium Tc 99m Sestamibi Injection is not indicated for breast cancer screening, to confirm the presence or absence of malignancy, and it is not an alternative to biopsy. Technetium Tc 99m Sestamibi, is a myocardial perfusion agent indicated for: detecting coronary artery disease by localizing myocardial ischemia (reversible defects) and infarction (non-reversible defects) ( 1 ) evaluating myocardial function and developing information for use in patient management decisions ( 1 )

For Myocardial Imaging: The suggested dose range for I.V. administration of Technetium Tc 99m Sestamibi in a single dose to be employed in the average patient (70 kg) is 370 to 1110 MBq (10 to 30 mCi). For Breast Imaging: The recommended dose range for I.V. administration of Technetium Tc 99m Sestamibi is a single dose of 740 to 1110 MBq (20 to 30 mCi). For Myocardial Imaging: The suggested dose range for I.V. administration of Technetium Tc 99m Sestamibi in a single dose to be employed in the average patient (70 kg) is 370 to 1110 MBq (10 to 30 mCi) ( 2 ). For Breast Imaging: The recommended dose range for I.V. administration of Technetium Tc 99m Sestamibi is a single dose of 740 to 1110 MBq (20 to 30 mCi) ( 2 ). 2.1 Image Acquisition Breast Imaging: It is recommended that images are obtained with a table overlay to separate breast tissue from the myocardium and liver, and to exclude potential activity that may be present in the opposite breast. For lateral images, position the patient prone with the isolateral arm comfortably above the head, shoulders flat against the table, head turned to the side and relaxed, with the breast imaged pendent through an overlay cutout. The breast should not be compressed on the overlay. For anterior images, position the patient supine with both arms behind the head. For either lateral or anterior images, shield the chest and abdominal organs, or remove them from the field of view. For complete study, sets of images should be obtained five minutes after the injection, and in the following sequence: Beginning five minutes after the injection of Technetium Tc 99m Sestamibi: ten-minute lateral image of breast with abnormality ten-minute lateral image of contralateral breast ten-minute anterior image of both breasts 2.2 Radiation Dosimetry The radiation doses to organs and tissues of an average patient (70 kg) per 1110 MBq (30 mCi) of Technetium Tc 99m Sestamibi injected intravenously are shown in Table 1. Table 1. Radiation Absorbed Doses from Tc 99m Sestamibi Estimated Radiation Absorbed Dose REST STRESS 2.0 hour void 4.8 hour void 2.0 hour void 4.8 hour void Organ rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq Breasts 0.2 2.0 0.2 1.9 0.2 2.0 0.2 1.8 Gallbladder Wall 2.0 20.0 2.0 20.0 2.8 28.9 2.8 27.8 Small Intestine 3.0 30.0 3.0 30.0 2.4 24.4 2.4 24.4 Upper Large Intestine Wall 5.4 55.5 5.4 55.5 4.5 44.4 4.5 44.4 Lower Large Intestine Wall 3.9 40.0 4.2 41.1 3.3 32.2 3.3 32.2 Stomach Wall 0.6 6.1 0.6 5.8 0.6 5.3 0.5 5.2 Heart Wall 0.5 5.1 0.5 4.9 0.5 5.6 0.5 5.3 Kidneys 2.0 20.0 2.0 20.0 1.7 16.7 1.7 16.7 Liver 0.6 5.8 0.6 5.7 0.4 4.2 0.4 4.1 Lungs 0.3 2.8 0.3 2.7 0.3 2.6 0.2 2.4 Bone Surfaces 0.7 6.8 0.7 6.4 0.6 6.2 0.6 6.0 Thyroid 0.7 7.0 0.7 2.4 0.3 2.7 0.2 2.4 Ovaries 1.5 15.5 1.6 15.5 1.2 12.2 1.3 13.3 Testes 0.3 3.4 0.4 3.9 0.3 3.1 0.3 3.4 Red Marrow 0.5 5.1 0.5 5.0 0.5 4.6 0.5 4.4 Urinary Bladder Wall 2.0 20.0 4.2 41.1 1.5 15.5 3.0 30.0 Total Body 0.5 4.8 0.5 4.8 0.4 4.2 0.4 4.2 Radiation dosimetry calculations performed by Radiation Internal Dose Information Center, Oak Ridge Institute for Science and Education, PO Box 117, Oak Ridge, TN 37831-0117. 2.3 Instructions for Preparation Preparation of the Technetium Tc 99m Sestamibi from the Kit for the Preparation of Technetium Tc 99m Sestamibi is done by the following aseptic procedure: General Procedure: a. Prior to adding the Sodium Pertechnetate Tc 99m Injection to the vial, inspect the vial carefully for the presence of damage, particularly cracks, and do not use the vial if found. Tear off a radiation symbol and attach it to the neck of the vial. b. Waterproof gloves should be worn during the preparation procedure. Remove the plastic disc from the vial and swab the top of the vial closure with alcohol to sanitize the surface. Boiling Water Bath Procedure: c. Place the vial in a suitable radiation shield with a fitted radiation cap. d. With a sterile shielded syringe, aseptically obtain additive-free, sterile, non-pyrogenic Sodium Pertechnetate Tc 99m Injection [925 to 5550 MBq, (25 to 150 mCi)] in approximately 1 to 3 mL. e. Aseptically add the Sodium Pertechnetate Tc 99m Injection to the vial in the lead shield. Without withdrawing the needle, remove an equal volume of headspace to maintain atmospheric pressure within the vial. f. Shake vigorously, about 5 to 10 quick upward-downward motions. g. Remove the vial from the lead shield and place upright in an appropriately shielded and contained boiling water bath, such that the vial is suspended above the bottom of the bath, and boil for 10 minutes. Timing for 10 minutes is begun as soon as the water begins to boil again. Do not allow the boiling water to come in contact with the aluminum crimp. h. Remove the vial from the water bath, place in the lead shield and allow to cool for fifteen (15) minutes. i. Using proper shielding, the vial contents should be visually inspected. Use only if the solution is clear and free of particulate matter and discoloration. j. Assay the reaction vial using a suitable radioactivity calibration system. Record the Technetium Tc 99m concentration, total volume, assay time and date, expiration time and lot number on the radioassay information label and affix the label to the shield. k. Store the reaction vial containing the Technetium Tc 99m Sestamibi at 15 °C to 25 °C (59 °F to 77 °F) until use; at such time the product should be aseptically withdrawn. Technetium Tc 99m Sestamibi should be used within six (6) hours of preparation. The vial contains no preservative. Note: Adherence to the above product reconstitution instructions is recommended. The potential for cracking and significant contamination exists whenever vials containing radioactive material are heated. This product is not to be used with the Recon-o-stat (thermal cycler) due to smaller vial size requirements of this heating device. Product should be used within six (6) hours after preparation. Final product with radiochemical purity of at least 90% was used in the clinical trials that established safety and effectiveness. The radiochemical purity was determined by the following method. 2.4 Determination of Radiochemical Purity in Technetium Tc 99m Sestamibi Obtain a Baker-Flex Aluminum Oxide coated, plastic TLC plate, #1 B-F, pre-cut to 2.5cm x 7.5cm. Dry the plate or plates at 100°C for 1 hour and store in a desiccator. Remove pre-dried plate from the desiccator just prior to use. Apply 1 drop of ethanol* using a 1 mL syringe with a 22 to 26 gauge needle, 1.5cm from the bottom of the plate. THE SPOT SHOULD NOT BE ALLOWED TO DRY. Add 2 drops of Technetium Tc 99m Sestamibi solution, side by side on top of the ethanol* spot. Return the plate to a desiccator and allow the sample spot to dry (typically 15 minutes). The TLC tank is prepared by pouring ethanol* to a depth of 3 to 4 mm. Cover the tank and let it equilibrate for ~10 minutes. Develop the plate in the covered TLC tank in ethanol* for a distance of 5 cm from the point of application. Cut the TLC plate 4 cm from the bottom and measure the Tc 99m activity in each piece by appropriate radiation detector. Calculate the % Tc 99m Sestamibi as: *The ethanol used in this procedure should be 95% or greater. Absolute ethanol (99%) should remain at ≥ 95% ethanol content for one week after opening if stored tightly capped, in a cool dry place. TLC Plate Diagram

None known. None known ( 4 ).

Adverse events were evaluated in 3741 adults who were evaluated in clinical studies. Of these patients, 3068 (77% men, 22% women, and 0.7 % of the patients' genders were not recorded) were in cardiac clinical trials and 673 (100% women) in breast imaging trials. Cases of angina, chest pain, and death have occurred [ see Warning and Precautions ( 5.1 ) ]. Adverse events reported at a rate of 0.5% or greater after receiving Technetium Tc 99m Sestamibi administration are shown in the following table: Table 2. Selected Adverse Events Reported in > 0.5 % of Patients Who Received Technetium Tc 99m Sestamibi in Either Breast or Cardiac Clinical Studies* Body System Breast Studies Cardiac Studies Women n = 673 Women n = 685 Men n = 2361 Total n = 3046 Body as a Whole 21 (3.1 %) 6 (0.9 %) 17 (0.7 %) 23 (0.8 %) Headache 11 (1.6 %) 2 (0.3 %) 4 (0.2 %) 6 (0.2 %) Cardiovascular 9 (1.3 %) 24 (3.5 %) 75 (3.2 %) 99 (3.3 %) Chest Pain/Angina 0 (0 %) 18 (2.6 %) 46 (1.9 %) 64 (2.1 %) ST Segment Changes 0 (0 %) 11 (1.6 %) 29 (1.2 %) 40 (1.3 %) Digestive System 8 (1.2 %) 4 (0.6 %) 9 (0.4 %) 13 (0.4 %) Nausea 4 (0.6 %) 1 (0.1 %) 2 (0.1 %) 3 (0.1 %) Special Senses 132 (19.6 %) 62 (9.1 %) 160 (6.8 %) 222 (7.3 %) Taste Perversion 129 (19.2 %) 60 (8.8 %) 157 (6.6 %) 217 (7.1 %) Parosmia 8 (1.2 %) 6 (0.9 %) 10 (0.4 %) 16 (0.5 %) * Excludes the 22 patients whose gender was not recorded. In the clinical studies for breast imaging, breast pain was reported in 12 (1.7 %) of the patients. In 11 of these patients the pain appears to be associated with biopsy/surgical procedures. The following adverse reactions have been reported in ≤ 0.5% of patients: signs and symptoms consistent with seizure occurring shortly after administration of the agent; transient arthritis; angioedema, arrhythmia, dizziness, syncope, abdominal pain, vomiting, and severe hypersensitivity characterized by dyspnea, hypotension, bradycardia, asthenia, and vomiting within two hours after a second injection of Technetium Tc 99m Sestamibi. A few cases of flushing, edema, injection site inflammation, dry mouth, fever, pruritis, rash, urticaria and fatigue have also been attributed to administration of the agent. The following adverse reactions have been reported in ≤ 0.5 % of patients: signs and symptoms consistent with seizure occurring shortly after administration of the agent; transient arthritis; angioedema, arrhythmia, dizziness, syncope, abdominal pain, vomiting, and severe hypersensitivity characterized by dyspnea, hypotension, bradycardia, asthenia, and vomiting within two hours after a second injection of Technetium Tc 99m Sestamibi. A few cases of flushing, edema, injection site inflammation, dry mouth, fever, pruritis, rash, urticaria and fatigue have also been attributed to administration of the agent ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Jubilant DraxImage Inc. at 1-888-633-5343or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Specific drug-drug interactions have not been studied. Specific drug-drug interactions have not been studied ( 7 ).